An "On Demand" canakinumab regimen for treating children with Colchicine-Resistant familial Mediterranean fever - A multicentre study.

OBJECTIVES: Canakinumab, a human monoclonal antibody targeted at interleukin-1 beta, has demonstrated safety and efficacy in preventing familial Mediterranean fever (FMF) attacks among individuals with colchicine-resistant (crFMF). The manufacturer orders prescribe monthly subcutaneous injections. However, a subset of our patients is treated with an "canakinumab on demand " (COD) strategy, with wider intervals between drug administrations. Therefore, we aimed to compare disease activity and drug safety between COD and "canakinumab fixed frequency" (CFF) policies. METHODS: This retrospective study collected data from three Israeli paediatric rheumatology centres, of children with crFMF who were treated with canakinumab. Epidemiological and clinical parameters, cumulative drug dosages, and adverse events were compared between children treated by both policies. RESULTS: Twenty-five (49 %) children were treated according to COD policy and 26 according to CFF policy. Demographic parameters and most of the disease features did not differ significantly between the groups. Both groups showed significant reduction in attacks after canakinumab introduction. The median number (interquartile range) of attacks per month did not differ significantly between the COD and CFF groups (0.33 (0.08, 0.58) and 0.13 (0, 0.5), respectively, p = 0.485 (even though, per definition, COD patients presumably had an attack before receiving the second canakinumab dose). The mean monthly dose was lower for the COD than the CFF group (1.13 ± 1.13 vs. 3.16 ± 1.46 mg/kg, p < 0.001). Adverse events were similar between the groups. CONCLUSION: For individuals with crFMF, COD compared to CFF policy can achieve similar efficacy and safety, with a lower accumulated canakinumab dose, rendering it less immunosuppressive and less expensive.

IgA vasculitis in adults, pediatrics and non-vasculitic IgA nephropathy, retrospective analysis from 2 centers.

Renal involvement represents the major long-term morbidity associated with IgA vasculitis (IgAV). Our aim was to evaluate clinical characteristics and long-term renal outcomes of IgAV in pediatrics and adults comparing to IgA nephropathy (IgAN). Our retrospective study included children and adults with IgAV and IgAN patients, admitted in a 13-year period (2007-2019) to rheumatology clinics and in hospital pediatric and internal medicine departments. We compared frequencies of clinical manifestations, laboratory findings, treatments, long-term outcomes at 1 year follow-up, including all-cause mortality and dialysis until the end of follow-up time. A total of 60 adult IgAV, 60 pediatric IgAV and 45 IgAN patients were evaluated. Adult IgAV patients were significantly older than IgAN patients (53.1 ±â€…17.4 years vs 45.1 ±â€…15.7 years respectively, P = .02) and had significantly higher rates of cardiovascular comorbidities. The risk and time to dialysis were similar among IgAN and adult IgAV groups. Yet, overall mortality at long term follow up was higher in IgAV adult group compared to IgAN. No dialysis or renal transplantation were reported in pediatric IgAV patients. IgAV and IgAN adult patients were comparable regarding risk of end stage renal disease. Of note, high mortality rates were observed among adult IgAV group.

Extreme Periodic Fever, Aphthous Stomatitis, Pharyngitis, Adenitis (PFAPA): a discrete group of patients.

OBJECTIVE: Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome is the most common periodic fever syndrome in children; by definition, episodes occur every 2 to 8 weeks. However, in a subset of our patients, we noticed a higher frequency of attacks, of less than 2 weeks, which we refer to as extreme PFAPA (ePFAPA). This group consisted of patients who were extreme upon presentation of PFAPA, and those who became extreme after initiation of abortive corticosteroid treatment. We aimed to characterize demographic and clinical features of ePFAPA, including the two groups, and to compare them to patients with non-extreme PFAPA (nPFAPA). STUDY DESIGN: The medical records of 365 patients with PFAPA who attended Schneider Children's Medical Center of Israel from March 2014 to April 2021 were reviewed. Patients with concomitant familial Mediterranean fever were excluded. Characteristics of the ePFAPA (including subgroups) and nPFAPA groups were compared using Wilcoxon rank sum, Pearson's chi-squared, and Fisher's exact tests. RESULTS: Forty-seven patients (12.9%) were identified as having ePFAPA. Among patients with ePFAPA, compared to patients with nPFAPA, the median (interquartile range) age at disease onset was earlier: 1.5 years (0.7-2.5) vs. 2.5 years (1.5-4.0), P < 0.001; and diagnosis was younger: 2.6 years (2.0-3.6) vs. 4.5 years (3.0-6.2), P < 0.001. A higher proportion of patients with ePFAPA than nPFAPA were treated with colchicine prophylaxis (53% vs. 19%, P < 0.001), but symptoms and signs during flares did not differ significantly between these groups. Demographic and clinical characteristics were similar between patients with ePFAPA from presentation of PFAPA (22, 47% of those with ePFAPA) and ePFAPA from after corticosteroid treatment. CONCLUSION: About half the patients categorized with ePFAPA syndrome already had extreme features upon presentation. Patients with ePFAPA compared to nPFAPA presented and were diagnosed at an earlier age.

Safety and Immunogenicity Following the Second and Third Doses of the BNT162b2 mRNA COVID-19 Vaccine in Adolescents with Juvenile-Onset Autoimmune Inflammatory Rheumatic Diseases: A Prospective Multicentre Study.

BACKGROUND: To explore the long-term safety and dynamics of the immune response induced by the second and third doses of the BNT162b2 mRNA COVID-19 vaccine in adolescents with juvenile-onset autoimmune inflammatory rheumatic diseases (AIIRDs) compared with healthy controls. METHODS: This international prospective study included adolescents with AIIRDs and controls vaccinated with two (AIIRDs n = 124; controls n = 80) or three (AIIRDs n = 64; controls n = 30) doses of the BNT162b2 vaccine, evaluated for vaccine side-effects, disease activity, COVID-19 breakthrough infection rates and severity, and anti-spike S1/S2 IgG antibody titers in a sample from both groups. RESULTS: The vaccination safety profile was favorable, with most patients reporting mild or no side-effects. The rheumatic disease remained stable at 98% and 100% after the second and third doses, respectively. The two-dose vaccine induced comparable seropositivity rates among patients (91%) and controls (100%), (p = 0.55), which declined within 6 months to 87% and 100%, respectively (p = 0.3) and increased to 100% in both groups after the third vaccine dose. The overall post-vaccination COVID-19 infection rate was comparable between patients and controls, 47.6% (n = 59) and 35% (n = 28), respectively; p = 0.5278, with most infections occurring during the Omicron surge. In relation to the last vaccination, time-to-COVID-19 infection was similar between patients and controls, at a median of 5.5 vs. 5.2 months, respectively (log-rank p = 0.1555). CONCLUSION: The safety profile of three doses of the BNT162b2 mRNA vaccine was excellent, with adequate humoral response and similar efficacy among patients and controls. These results support the recommendation for vaccinating adolescents with juvenile-onset AIIRDs against COVID-19.

Infantile Takayasu: clinical features and long-term outcome.

OBJECTIVES: Takayasu arteritis (TAK) is a large-vessel vasculitis rarely reported in children and infants. Most articles on paediatric TAK have not focused on infants. We present the largest case series of infantile TAK, aiming to identify its demographic and clinical characteristics and compare them with existing data on older children. METHODS: We conducted an international multicentre retrospective cohort study. Epidemiological and clinical data were collected from patients' charts from six rheumatology centres. All patients met both the EULAR/PReS 2008 criteria and the 1990 ACR/EULAR criteria and were diagnosed with TAK at age <5 years. RESULTS: Twelve patients were included (50% female). Median age of symptom onset was 11 months, with a diagnostic delay of 4 months. The most common symptoms at presentation were hypertension, blood pressure differences between limbs, and fever. The most commonly involved arteries were the abdominal aorta and renal artery. Medications included steroids, conventional and biologic DMARDs, and other immunosuppressive therapies. Half of the patients received biologic agents, of which infliximab had the highest complete remission rate (40%). Other medications resulting in complete remission were CYC (40%) and MTX (38%). Invasive procedures were required for 58% of patients. The most common complications were cardiac (50%), stroke (42%), and serious infections (33%). No patients died. CONCLUSION: This study presents the largest series of infantile TAK. Compared with other reported series on older children, infants with TAK have more severe disease and were more likely to receive biologic agents, develop complications, and require invasive interventions.

Risk factors for haemodynamic compromise in multisystem inflammatory syndrome in children: a multicentre retrospective study.

OBJECTIVES: To identify predictors of a severe clinical course of multisystem inflammatory syndrome in children (MIS-C), as defined by the need for inotropic support. METHODS: This retrospective study included patients diagnosed with MIS-C (according to the CDC definition) in nine Israeli and one US medical centre between July 2020 and March 2021. Univariate and multivariate regression models assessed odds ratio (OR) of demographic, clinical, laboratory and imaging variables during admission and hospitalization for severe disease. RESULTS: Of 100 patients, 61 (61%) were male; mean age 9.65 (4.48) years. Sixty-five patients were hypotensive, 44 required inotropic support. Eleven patients with MIS-C fulfilled Kawasaki disease diagnostic criteria; 87 had gastrointestinal symptoms on admission. Echocardiographic evaluation showed 10 patients with acute coronary ectasia or aneurysm, and 37 with left ventricular dysfunction. In a univariate model, left ventricular dysfunction was associated with severe disease [OR 4.178 (95% CI 1.760, 9.917)], while conjunctivitis [OR 0.403 (95% CI 0.173, 0.938)] and mucosal changes [OR 0.333 (95% CI 0.119, 0.931)] at admission were protective. Laboratory markers for a severe disease course were low values of haemoglobin, platelets, albumin and potassium; and high leukocytes, neutrophils, troponin and brain natriuretic peptide. In multivariate analysis, central nervous system involvement and fever >39.5°C were associated with severe disease. Mucosal involvement showed 6.2-fold lower risk for severe disease. Low haemoglobin and platelet count, and elevated C-reactive protein and troponin levels were identified as risk factors for severe disease. CONCLUSION: Key clinical and laboratory parameters of MIS-C were identified as risk factors for severe disease, predominantly during the disease course and not at the time of admission; and may prompt close monitoring, and earlier, more aggressive treatment decisions. Patients presenting with a Kawasaki-like phenotype were less likely to require inotropic support.

Case Series of Myocarditis Following mRNA COVID Vaccine Compared to Pediatric Multisystem Inflammatory Syndrome: Multicenter Retrospective Study.

INTRODUCTION: Since the development of COVID-19 vaccines, more than 4.8 billion people have been immunized worldwide. Soon after vaccinations were initiated, reports on cases of myocarditis following the second vaccine dose emerged. This study aimed to report our experience with adolescent and young adults who developed post-COVID-19 vaccine myocarditis and to compare these patients to a cohort of patients who acquired pediatric inflammatory multisystem syndrome (PIMS/PIMS-TS) post-COVID-19 infection. METHODS: We collected reported cases of patients who developed myocarditis following COVID-19 vaccination (Pfizer mRNA BNT162b2) from all pediatric rheumatology centers in Israel and compared them to a cohort of patients with PIMS. RESULTS: Nine patients with post-vaccination myocarditis were identified and compared to 78 patients diagnosed with PIMS. All patients with post-vaccination myocarditis were males who developed symptoms following their second dose of the vaccine. Patients with post-vaccination myocarditis had a shorter duration of stay in the hospital (mean 4.4 ± 1.9 vs. 8.7 ± 4.7 days) and less myocardial dysfunction (11.1% vs. 61.5%), and all had excellent outcomes as compared to the chronic changes among 9.2% of the patients with PIMS. CONCLUSION: The clinical course of vaccine-associated myocarditis appears favorable, with resolution of the symptoms in all the patients in our cohort.

PFAPA flares observed during COVID outbreak: can emotional stress trigger PFAPA attacks? A multicenter cohort study.

OBJECTIVE: It is common knowledge among clinicians who treat PFAPA (Periodic Fever, Aphthous Stomatitis, Pharyngitis, Adenitis) patients that emotional stress can trigger PFAPA attacks similarly to other autoinflammatory diseases. However, it has never been proved scientifically. Our aim was to examine whether emotional stress serves as a trigger for PFAPA attacks. METHODS: Patients aged 3-12 years, with active PFAPA, from two Israeli medical centers were enrolled to this study. Patient's parents were reached via phone calls in two occasions: a stressful period related to the COVID-19 pandemic restrictions and a less stressful period. In both times they were asked to report occurrence of PFAPA attacks in the preceding 2 weeks. The relative stress levels of the two periods were validated by an emotional distress scale questionnaire. The significance level was set at 0.05. RESULTS: Mean age was 7.28 ± 2.7 for the 99 paediatric patients enrolled in the study. Scores for the mean emotional distress questionnaire were statistically significant higher in the stressful period compared to the less stressful period (35.6 ± 8.1 vs. 32.1 ±7.7, respectively, P = 0.047). In the stressful period, 41 (38.7%) reported at least one attack during the preceding 2 weeks, compared to 24 (22.6%) in the less stressful period (p = 0.017). CONCLUSION: PFAPA flares during COVID-19 outbreak are described. This study is the first to suggest that emotional stress is associated with PFAPA attacks.

Magnetic resonance findings may aid in diagnosis of protracted febrile myalgia syndrome: a retrospective, multicenter study.

BACKGROUND: Protracted febrile myalgia syndrome (PFMS) is a rare complication of Familial Mediterranean fever (FMF). The diagnosis is based on clinical symptoms and is often challenging, especially when PFMS is the initial manifestation of FMF. The aim of this report was to describe the magnetic resonance imaging (MRI) findings in pediatric patients with PFMS. RESULTS: There were three girls and two boys ranging in age from 6 months to 16 years, all of Mediterranean ancestry. Three had high-grade fever, and all had elevated inflammatory markers. MRI of the extremities yielded findings suggestive of myositis, which together with the clinical picture, normal CPK levels, and supporting family history of FMF, suggested the diagnosis of PFMS. Out of most common MEFV mutations tested, one patient was homozygous for M694V mutation, three were heterozygous for M694V mutation, and one was compound heterozygous for the M694V and V726A mutations. CONCLUSIONS: MRI may serve as an auxiliary diagnostic tool in PFMS.

Tofacitinib in juvenile idiopathic arthritis: a double-blind, placebo-controlled, withdrawal phase 3 randomised trial.

BACKGROUND: Tofacitinib is an oral Janus kinase inhibitor. This trial assessed the efficacy and safety of tofacitinib versus placebo in patients with polyarticular course juvenile idiopathic arthritis (JIA). METHODS: This double-blind, withdrawal phase 3 trial enrolled patients with polyarticular course JIA (extended oligoarthritis, rheumatoid factor-positive or rheumatoid factor-negative polyarthritis, or systemic JIA without active systemic features) aged 2 years to younger than 18 years, and was done at 64 centres of the Paediatric Rheumatology International Trials Organisation and Pediatric Rheumatology Collaborative Study Group networks in 14 countries. Patients with psoriatic arthritis or enthesitis-related arthritis were enrolled for exploratory endpoints. During part 1 of the study, patients received oral open-label tofacitinib (weight-based doses; 5 mg twice daily or lower) for 18 weeks. Patients achieving at least JIA/American College of Rheumatology 30 response were randomly assigned (1:1) using an Interactive Response Technology system to continue tofacitinib or switch to placebo in part 2 of the study for 26 weeks. The primary endpoint was JIA flare rate by week 44 in part 2 in patients with polyarticular course JIA; the intention-to-treat principle was applied. Safety was evaluated throughout part 1 and part 2 of the study in all patients who received one dose or more of study medication. This trial is registered with ClinicalTrials.gov, NCT02592434. FINDINGS: Between June 10, 2016, and May 16, 2019, of 225 patients enrolled, 184 (82%) patients had polyarticular course JIA, 20 (9%) had psoriatic arthritis, and 21 (9%) had enthesitis-related arthritis. 147 (65%) of 225 patients received concomitant methotrexate. In part 2, 142 patients with polyarticular course JIA were assigned to tofacitinib (n=72) or placebo (n=70). Flare rate by week 44 was significantly lower with tofacitinib (21 [29%] of 72 patients) than with placebo (37 [53%] of 70 patients; hazard ratio 0·46, 95% CI 0·27-0·79; p=0·0031). In part 2 of the study, adverse events occurred in 68 (77%) of 88 patients receiving tofacitinib and 63 (74%) of 85 in the placebo group. Serious adverse events occurred in one (1%) and two (2%), respectively. In the entire tofacitinib exposure period, 107 (48%) of 225 patients had infections or infestations. There were no deaths during this study. INTERPRETATION: The results of this pivotal trial show that tofacitinib is an effective treatment in patients with polyarticular course JIA. New oral therapies are particularly relevant for children and adolescents, who might prefer to avoid injections. FUNDING: Pfizer.

A novel loss-of-function mutation in LACC1 underlies hereditary juvenile arthritis with extended intra-familial phenotypic heterogeneity.

OBJECTIVE: To investigate phenotypic and molecular characteristics of a consanguineous family with autosomal-recessive, polyarticular, juvenile isiopathic arthriris (JIA) with extra-articular manifestations, including renal amyloidosis and Crohn's disease, associated with a novel homozygous truncating variant in LACC1. METHODS: Whole exome sequencing (WES) or targeted Sanger verification were performed in 15 participants. LACC1 expression and cytokine array were analysed in patient-derived and CRISPR/Cas9-generated LACC1-knockout macrophages (Mϕ). RESULTS: A homozygous truncating variant (p.Glu348Ter) in LACC1 was identified in three affected and one asymptomatic family member, and predicted harmful by causing premature stop of the LACC1 protein sequences, and by absence from ethnically-matched controls and public variation databases. Expression studies in patient-derived macrophages (Mϕ) showed no endogenous p.Glu348Ter-LACC1 RNA transcription or protein expression, compatible with nonsense-mediated mRNA decay. WES analysis in the asymptomatic homozygous subject for p. Glu348Ter-LACC1 detected an exclusive heterozygous variant (p.Arg928Gln) in complement component C5. Further complement activity analysis suggested a protective role for the p.Arg928Gln-C5 variant as a phenotypic modifier of LACC1-associated disease. Finally, cytokine profile analysis indicated increased levels of pro-inflammatory cytokines in LACC1-disrupted as compared with wild-type Mϕ. CONCLUSIONS: Our findings reinforce the role of LACC1 disruption in autosomal-recessive JIA, extend the clinical spectrum and intra-familial heterogeneity of the disease-associated phenotype, indicate a modulatory effect of complement factor C5 on phenotypic severity, and suggest an inhibitory role for wild-type LACC1 on pro-inflammatory pathways.

Familial Periodic Fever, Aphthous Stomatitis, Pharyngitis and Adenitis Syndrome; Is It a Separate Disease?

Introduction: Periodic Fever, Aphthous Stomatitis, Pharyngitis, Adenitis (PFAPA) is the most common periodic fever syndrome in the pediatric population, yet its pathogenesis is unknown. PFAPA was believed to be sporadic but family clustering has been widely observed. Objective: To identify demographic and clinical differences between patients with PFAPA and a positive family history (FH+) as compared to those with no family history (FH-). Methods: In a database comprising demographic and clinical data of 273 pediatric PFAPA patients treated at two tertiary centers in Israel, 31 (14.3%) had FH+. Data from patients with FH+ were compared to data from those with FH-. Furthermore, family members (FMs) of those with FH+ were contacted via telephone for more demographic and clinical details. Results: The FH+ group as compared to the FH- group had more myalgia (56 vs. 19%, respectively, p = 0.001), headaches (32 vs. 2%, respectively, p = 0.016), and a higher carrier frequency of M694V mutation (54% vs. 25%, respectively, p = 0.05). Colchicine was seen to be a more beneficial treatment for the FH+ group as compared to the FH- group; however, with no statistical significance (p = 0.096). FMs displayed almost identical characteristics to patients in the FH+ group except for greater arthralgia during flares (64 vs. 23%, respectively, p = 0.008), and compared to the FH- group they had more oral aphthae (68 vs. 43%, respectively, p = 0.002), myalgia/arthralgia (64 vs. 19%/16%, respectively, p < 0.0001), and higher rates of FH of Familial Mediterranean fever (FMF) (45 vs.15%, respectively, p = 0.003). Conclusions: Our findings suggest that patients with a FH+ likely experience a different subset of disease with higher frequency of family history of FMF, arthralgia, myalgia, and might have a better response to colchicine compared to FH-. Colchicine prophylaxis for PFAPA should be considered in FH+.

Atypical cardiopulmonary manifestations in pediatric Behçet's disease.

BACKGROUND: Behçet's disease (BD) is a multisystem autoinflammatory disease of unknown etiology. Cardiopulmonary involvement is rare, especially in young patients, and carries high morbidity and mortality rates. AIM: Of 26 patients with pediatric BD enlisted in our center, we encountered three patients with severe atypical cardiorespiratory presentations. Our aim was to describe the manifestations and the course that led to the diagnosis of BD. RESULTS: Three adolescents presented with intracardiac thrombi and left anterior descending obstruction causing myocardial infarction, pulmonary artery aneurysm with pulmonary embolism in situ, and suspected epiglottitis. Two patients had a delayed diagnosis of BD, and all had a good response to anti-inflammatory agents. CONCLUSIONS: This study demonstrated that pediatric BD is associated with atypical cardiopulmonary manifestations which maybe life threatening. Since diagnosis maybe challenging, a high index of suspicion is needed especially in young patients, to promptly diagnose and treat these complications. Cardiopulmonary signs and symptoms, though uncommon, maybe the first manifestation and a clue to the diagnosis of this rare disease.

Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Adenitis Syndrome - Is It Related to Ethnicity? An Israeli Multicenter Cohort Study.

OBJECTIVES: To evaluate the ethnic distribution of Israeli patients with the syndrome of periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA). STUDY DESIGN: The medical records of patients with PFAPA attending 2 pediatric tertiary medical centers in Israel from March 2014 to March 2019 were retrospectively reviewed. Patients with concomitant familial Mediterranean fever were excluded. Ethnicity was categorized as Mediterranean, non-Mediterranean, and multiethnic. Findings were compared with patients with asthma under treatment at the same medical centers during the same period. RESULTS: The cohort included 303 patients with PFAPA and 475 with asthma. Among the patients with PFAPA, 178 (58.7%) were of Mediterranean descent (Sephardic Jews or Israeli Arabs), 96 (33.0%) were multiethnic, and 17 (5.8%) were of non-Mediterranean descent (all Ashkenazi Jews). Patients with PFAPA had a significantly higher likelihood of being of Mediterranean descent than the patients with asthma (58.7% vs 35.8%; P < .0001). The Mediterranean PFAPA subgroup had a significantly earlier disease onset than the non-Mediterranean subgroup (2.75 ± 1.7 vs 3.78 ± 1.9 years, P < .04) and were younger at disease diagnosis (4.77 ± 2.3 vs 6.27 ± 2.9 years, P < .04). CONCLUSIONS: PFAPA was significantly more common in patients of Mediterranean than non-Mediterranean descent. Further studies are needed to determine the genetic background of these findings.

Characteristics of pediatric Behçet's disease in Turkey and Israel: A cross-sectional cohort comparison.

BACKGROUND: Behçet's disease (BD) is a variable vessel vasculitis which is rare in children. OBJECTIVE: We aimed to compare the main characteristics of pediatric BD patients from Turkey versus Israel. METHODS: Three centers from Turkey and two centers from Israel participated in this study. The BD diagnosis was before 16 years of age and based on expert opinion. Disease activity was assessed with BD current activity form (BDCAF). RESULTS: A total of 205 patients were included (165 from Turkey; 40 from Israel). HLA-B51 positivity (68.3% vs. 46.2%, p = 0.028), male gender (52% vs. 30%, p = 0.012), and skin involvement (55.2% vs. 22.5%, p<0.001) were more frequent among patients from Turkey compared to patients from Israel. Tests of pathergy and HLA-B51 were more frequently performed in patients from Turkey than patients from Israel (93.3% vs. 32.5%, p<0.001 and 97.6% vs. 65%, p<0.001; respectively). For BD classification in the whole group, International Criteria for BD (ICBD) had the highest sensitivity (73.2%), followed by pediatric BD (PED-BD) (47.8%), and The International Study Group (ISG) (42%) criteria sets. The most commonly prescribed drug was colchicine in the whole group (96.6%). Significantly more patients were treated with corticosteroids (50% vs. 28.5%, p = 0.006), methotrexate (17.5% vs. 3%, p = 0.002), and nonsteroidal anti-inflammatory drugs (12.5% vs. 1.8%, p = 0.007) in Israel than in Turkey. The median BDCAF values were higher at the first visit for patients from Turkey compared to those in Israel (4 vs. 2, p<0.001). CONCLUSION: This is the largest cohort of pediatric BD reported to date. The disease characteristics significantly differ among pediatric BD patients from Turkey and Israel, which may be due to different ethnicity and environmental factors.

Autologous Hematological Stem Cell Transplantation for Systemic Sclerosis in Israel.

BACKGROUND: Autologous hematological stem cell transplantation (HSCT) is a novel therapy for systemic sclerosis (SSc) that has been validated in three randomized controlled trials. OBJECTIVES: To report the first Israeli experience with HSCT for progressive SSc and review the current literature. METHODS: Five SSc patients who were evaluated in our department and were treated by HSCT were included. Medical records were evaluated retrospectively. Demographic, clinical, and laboratory data were recorded. Continuous data are presented as the mean ± standard deviation. Categorical variables are presented as frequencies and percentages. RESULTS: Five SSc patients were treated with HSCT. Four patients were adults (mean age 53 ± 12 years) and one was a 12-year-old pediatric patient. All patients were female. HSCT was initiated 1.4 ± 0.8 years after diagnosis. Two patients were RNA POLIII positive, two were anti-topoisomerase 1 positive, and one only antinuclear antibodies positive. All patients had skin and lung involvement. The mean modified Rodnan Skin Score was 29 ± 4.7 before HSCT, which improved to 10.4 ± 9.6 after HSCT. The forced vital capacity improved from 68 ± 13% to 90 ± 28%. Diffusing capacity of the lungs for carbon monoxide increased by 6%. Among severe adverse events were cyclophosphamide-related congestive heart failure, antithymocyte globulin-related capillary leak syndrome, and scleroderma renal crisis. All symptoms completely resolved with treatment without sequela. No treatment related mortality was recorded. CONCLUSIONS: HSCT is an important step in the treatment of progressive SSc in Israel. Careful patient selection reduces treatment related morbidity and mortality.

Familial Mediterranean Fever Is Commonly Diagnosed in Children in Israel with Periodic Fever Aphthous Stomatitis, Pharyngitis, and Adenitis Syndrome.

OBJECTIVES: To describe a cohort of pediatric patients diagnosed with periodic fever aphthous stomatitis, pharyngitis and adenitis (PFAPA) and familial Mediterranean fever (FMF) and compare them with children diagnosed solely with PFAPA (sPFAPA). STUDY DESIGN: Clinical, laboratory, and genetic data of all pediatric patients diagnosed with sPFAPA or PFAPA/FMF were retrospectively collected from 2 primary Israeli medical referral centers and compared. RESULTS: Of 270 patients with PFAPA, more than one-half were of Mediterranean ancestry. Among patients with PFAPA, 51 (18.9%) also were diagnosed with FMF (PFAPA/FMF). Genetic data on the 9 most common MEFV variants were available for 45 children (88%) in the PFAPA/FMF group. Two variants were found in 15 children (33.3 %), 1 variant was found 27 patients (60%), and 3 patients (6.6%) had no variants. Abdominal pain, myalgia, and arthralgia each were more commonly reported in the PFAPA/FMF group compared with the sPFAPA group (90% vs 49% [P < .0001]; 46% vs 23% [P = .02]; and 30% vs 17% [P = .049], respectively). Colchicine was more commonly prescribed for the PFAPA/FMF group compared with the sPFAPA group (82% vs 29%; P < .0001), but alleviation of PFAPA symptoms with colchicine was similar between groups (75% vs 63%; P = .23). CONCLUSION: We show a strong association between 2 common autoinflammatory syndromes, PFAPA and FMF, in patients from Mediterranean ancestry. Clinicians should be aware that presentation of 1 disease may clinically evolve into another. The association between PFAPA and FMF poses the question similar pathogenesis and genetic influence of the MEFV gene on PFAPA.

Juvenile Psoriatic Arthritis: A Report from the GRAPPA 2017 Annual Meeting.

Juvenile psoriatic arthritis (JPsA), a subtype of juvenile idiopathic arthritis (JIA), constitutes 5% of JIA. The literature is inconsistent regarding features of JPsA, and physicians debate whether it is a distinct entity within JIA. A biphasic age of onset distribution has been noted. Early-onset disease is characterized by female predominance, small joint involvement, dactylitis, and positive antinuclear antibodies. Late-onset JPsA resembles adult-onset psoriatic arthritis (PsA), with male predominance, psoriasis, enthesitis, and axial disease. Recent studies report improved outcomes, likely due to the widespread use of traditional and biologic disease-modifying antirheumatic drugs. Conflicting HLA associations have been reported in JPsA, but notably both HLA class I and II allele associations are suggested. Similar to PsA cohorts, subjects with JPsA have a lower frequency of a protective interleukin 23R allele than controls or other JIA subtypes. Data in the Childhood Arthritis and Rheumatology Research Alliance (CARRA) patient registry suggest the aggressive characteristics of JPsA: 24.6% of children have joint damage 4.6 years after symptom onset. Pediatric and adult PsA classification criteria define different JPsA cohorts within the registry and support a previous suggestion that the International League of Associations for Rheumatology criteria for JPsA may be overly stringent. Increased collaboration between pediatric and adult physicians and comparative research on these clinically related conditions are warranted.

Is palindromic rheumatism amongst children a benign disease?

BACKGROUND: Palindromic rheumatism is an idiopathic, periodic arthritis characterized by multiple, transient, recurring episodes. Palindromic rheumatism is well-characterized in adults, but has never been reported in pediatric populations. The aim of this study was to characterize the clinical features and outcomes of a series of pediatric patients with palindromic rheumatism. METHODS: We defined clinical criteria for palindromic rheumatism and reviewed all clinical visits in three Pediatric Rheumatology centers in Israel from 2006through 2015, to identify patients with the disease. We collected retrospective clinical and laboratory data on patients who fulfilled the criteria, and reviewed their medical records in order to determine the proportion of patients who had developed juvenile idiopathic arthritis. RESULTS: Overall, 10 patients were identified. Their mean age at diagnosis was 8.3 ± 4.5 years and the average follow-up was 3.8 ± 2.7 years. The mean duration of attacks was 12.2 ± 8.4 days. The most frequently involved joints were knees. Patients tested positive for rheumatoid factor in 20% of cases. One patient developed polyarticular juvenile idiopathic arthritis after three years of follow-up, six patients (60%) continued to have attacks at their last follow-up and only three children (30%) achieved long-term remission. CONCLUSIONS: Progression to juvenile idiopathic arthritis is rare amongst children with palindromic rheumatism and most patients continued to have attacks at their last follow-up. Longer follow-up periods are required to predict the long-term outcomes of pediatric patients with palindromic rheumatism.